Although both ceramide and interleukin-ll] convert-apoptosis [15][16][17][18]. However, ICE itself might not be a true mammalian Ced-3 counterpart because apoptosis proceeds aling enzyme (ICE) family proteases are key molecules during apoptosis, their relationship remains to be elucidated. We report most normally in ICE-deficient mice [19,20]. So far at least here that cell-permeable ceramide induced cleavage and activaseven mammalian Ced-3 homologues have been identified, tion of CPP32, a Ced-3/ICE-like protease, but not ICE. , especially the death domain, but not Apoptosis is a well-regulated process of cell death that is TNFRII(p75), raising the possibility that ceramide and ICEimportant in events such as embryogenesis, cell growth conlike proteases exist in the same signaling pathway. We theretrol and lymphocyte repertoire formation. Recent investigafore addressed this question in the present study and demontions have revealed that there are several key pathways in strated that CPP32 acts downstream of ceramide and its actiapoptotic signal transduction, including the sphingomyelinvation is required for ceramide-induced apoptosis. ceramide pathway [1,2] and the pathway involving interleukin-l~ converting enzyme (ICE)/Ced-3 family proteases [3].2. Materials and methods Ceramide is a newly identified lipid second messenger that is generated through the hydrolysis of sphingomyelin by 2.1. Reagents and cell lines sphingomyelinases (SMase) [1,2]. Signals from cell surface re-N-Acetyl ceramide (C2-ceramide) was purchased from Wako (Osaceptors such as Fas (CD95/Apol) [4][5][6][7] and tumor necrosis ka), C2-dihydroceramide from Calbiochem and dioctanoylglycerol factor receptor (TNFR) [8][9][10][11] activate SMase and generate from Sigma, and dissolved in ethanol. The final ethanol concentration in the culture medium was always less than 0.1%. Mouse IgM anticeramide, even in the cell-free system [12]. Synthetic cellhuman Fas monoclonal antibody (CH-11) was purchased from Medpermeable ceramide can mimic such apoptosis. This cytotoxic ical Biological Laboratories (Nagoya) and anti-CPP32 monoclonal effect is specific because structural analogues such as dihydroantibody from Transduction Laboratories. Tetrapeptide inhibitors ceramide do not induce apoptosis [13,14]. These data suggest for CPP32 (Ac-DEVD-CHO) and ICE (Ac-YVAD-CHO), and tetrathat ceramide is a physiological mediator of Fas-and TNFRpeptide substrates for CPP32 (Ac-DEVD-AMC) and ICE (Ac-YVAD-AMC) [22,27] were purchased from Peptide Industries (Osamediated apoptosis, ka) and dissolved in DMSO. The human T cell line, Jurkat, was ICE family proteases, which are mammalian Ced-3 homomaintained in RPMI 1640 medium containing 10% fetal calf serum logues, have also been implicated in Fas-and TNF-mediated (FCS). An anti-Fas-resistant (FR) subline of Jurkat was established by culturing wild-type Jurkat cells in the presence of 100 ng/ml antiFas (CH-11) for 1 month. *Corresponding author. Fax: (81) (3) 5803-0131.2.2. Immunoblotting of CPP32 **Research fellow o...

Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.

Objective. To establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan. Methods. Data from patients with RA (n ‫؍‬ 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case-control study to compare patients with and without PCP were performed. Results. The median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived. Conclusion. PCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy.

This consistency of pathologic findings and uniformity of courses indicates that aquaporin 4-specific autoantibodies as the initiator of the neuromyelitis optica (NMO) lesion consistently play an important common role in the pathogenicity through the entire course, consisting of both limited and definite forms, and NMO continuously displays homogeneity of pathogenic effector immune mechanisms through terminal stages, whereas multiple sclerosis should be recognized as the heterogeneous 2-stage disease that could switch from inflammatory to degenerative phase. This report is a significant description comparing the pathologic and immunologic data of limited NMO with those of definite NMO.